Compositions and methods for the treatment of inflammatory conditions

ABSTRACT

Embodiments of the invention relate to methods and compositions for treating symptoms related to inflammatory conditions and to methods and compositions for treating inflammatory components of common cold, utilizing various method of administration of X-ray contrast media (CM).

RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationSer. No. 60/914,642, filed on Apr. 27, 2007, and U.S. ProvisionalApplication Ser. No. 60/981,093, filed on Oct. 18, 2007 by Elliott C.Lasser and both entitled “COMPOSITIONS AND METHODS FOR THE TREATMENT OFINFLAMMATORY CONDITIONS,” each of which is hereby expressly incorporatedby reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Embodiments of the invention relate to methods and compositions fortreating symptoms related to inflammatory conditions and to methods andcompositions for treating inflammatory components of common cold,utilizing various method of administration of X-ray contrast media (CM).

2. Description of the Related Art

Inflammatory conditions afflict large numbers of individuals each yearon an acute or chronic basis. While inflammatory responses are usuallycomponents of the host's innate immune response, hyperactivity of theseresponses can result in mild, moderate, or extreme discomfort.Inflammatory conditions include those related to the skin, bronchi,colon, esophagus, for example. Ongoing research and development effortshave sought anti-inflammatory medications to treat the conditions.Steroid agents and various ephedrine compositions have been effectivelyused, but with the downside of various adverse side effects and in somecases rebound effects. Non-steroidal anti-inflammatory agents (i.e.,NSAIA), antihistamine, recombinant antibodies and other formulationshave been used with the hope of reducing the concentration of cytokinesand chemokines that produce the irritant effects in moderate and extremehyperimmune responses. While these have had various degrees of success,they vary in their potential to address issues such as immediacy ofeffect, cost, and adverse effects. There continues to be a need forsimple, cheap, low molecular weight compounds to treat inflammatoryconditions and also to treat inflammatory components of the common cold.

SUMMARY OF THE INVENTION

Some embodiments relate to methods of treating a skin inflammatorycondition in a mammal in need thereof which methods can includecontacting at least part of the skin of a mammal with a therapeuticallyeffective amount of a composition that includes an X-ray contrast media.The methods further can include, for example, identifying the mammal asa mammal that suffers from a condition related to skin inflammation ordermatitis (e.g., including atopic dermatitis). For example, thecondition can be eczema, dermatosis, insect bite reaction, sunburn,inflammation caused by graft v. host disease, inflammation caused byimmunobullous disease, other skin allergen reactions, and the like. Theskin allergen reaction can be, for example, a reaction resulting from avaccine, resulting from a sensitizing antigen, and the like. In someaspects the dermatosis can be psoriasis. In some aspects, psoriasis canbe specifically excluded from the methods described herein. Also, insome aspects the skin allergen can be, for example, poison ivy, poisonoak, poison sumac, grass allergen, dust allergen, pet allergens, and thelike. Further, the skin allergen can be a cleaning solution (includinge.g., shampoo), a detergent, a cosmetic, a perfume, an industrialchemical, a latex rubber, and the like. In some embodiments, any one ormore of the skin inflammatory conditions, skin inflammatory indicationslisted herein or one or more of the allergens can be specificallyexcluded from the methods and compositions.

In some embodiments the composition can be formulated as a topicalformulation, for example, a gel formulation, a cream formulation, alotion formulation, a paste formulation, an ointment formulation, an oilformulation, a foam formulation, a shampoo, a soap and the like. In someaspects, the topical compositions can be formulated to be absorbed,including to be substantially absorbed, by an epidermal layer of theskin. For example the topical compositions can include an absorptionemollient. The topical formulation further can include, for example,water, petrolatum, glycerin, propylene glycol, benzyl alcohol, magnesiumaluminum silicate, and tocopherol linoleate, castor oil, ethyleneglycol, monobutyl ether, diethylene glycol monoethyl ether, corn oil,dimethyl sulfoxide, ethylene glycol, isopropanol, soybean oil, glycerin,zinc oxide, titanium dioxide, glycerin, butylene glycol, cetyl alcohol,sodium hyaluronate and the like. Also, in some aspects the topicalformulation can include a preservative. For example, the preservativecan be at least one of benzalkonium chloride, benzoxonium chloride,benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridiniumchloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuricnitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben,propylparaben, chlorobutanol, benzyl alcohol, phenyl ethyl alcohol,chlorohexidine, polyhexamethylene biguanide, sodium perborate,imidazolidinyl urea, sorbic acid, Purite®), Polyquart®), sodiumperborate tetrahydrate, and the like. In some aspects, the topicalformulation can include a preservative that can be a quaternary ammoniumcompound, an alkyl-mercury salt of thiosalicylic acid, a paraben, analcohol, a biguanide derivative, a stabilized oxychloro complex, apolyglycol-polyamine condensation resin, a stabilized hydrogen peroxideand the like. In some embodiments the quaternary ammonium compound canbe a benzalkonium chloride, for example trimethyl benzyl ammoniumchloride and the like. In some aspects, one or more of the above-listedingredients can be specifically excluded from some of the compositionsand methods.

Some embodiments relate to methods of treating inflammation of the upperrespiratory track/bronchi in a mammal in need thereof, which methods caninclude contacting at least part of the upper respiratory tract/bronchiof a mammal with a therapeutically effective amount of a compositioncomprising an X-ray contrast media. The methods further can include, forexample, identifying the mammal as a mammal that suffers from acondition related to inflammation of the upper respiratorytrack/bronchi. For example, the condition can be allergic asthma,allergic bronchitis, asthmatic bronchitis, and bronchoconstriction. Insome embodiments, any one or more of the upper respiratory track/bronchiinflammatory conditions listed herein can be specifically excluded fromthe methods and compositions.

In some embodiments the composition can be formulated as an aerosolformulation. The aerosol formulated can be formulated to be absorbed,including substantially absorbed, by a bronchus. In some aspects, theaerosol composition can include an X-ray contrast media and anaerosolized pharmaceutically acceptable carrier solution or dry powder.For example, the aerosol formulations can include,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, or carbon dioxide. The aerosol formulationsfurther can include a preservative. The preservative can be, forexample, a quaternary ammonium compound, an alkyl-mercury salt ofthiosalicylic acid, a paraben, an alcohol, a biguanide derivative, astabilized oxychloro complex, a polyglycol-polyamine condensation resin,a stabilized hydrogen peroxide, and the like. For example, thepreservative can be at least one of benzalkonium chloride, benzoxoniumchloride, benzethonium chloride, cetrimide, sepazonium chloride,cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal,phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate,methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodiumperborate, imidazolidinyl urea, sorbic acid, Purite®), Polyquart®),sodium perborate tetrahydrate and the like. In some embodiments thequaternary ammonium compound can be a benzalkonium chloride, for exampletrimethyl benzyl ammonium chloride and the like. In some aspects, theaerosol formulations can be used in a nebulizer. Also, in some aspects,for example, the aerosol formulations can be used in an inhaler. In someaspects, one or more of the above-listed ingredients can be specificallyexcluded from some of the compositions and methods.

Some embodiments relate to methods of treating a colon inflammatorycondition in a mammal in need thereof, which methods can includecontacting at least part of the colon of a mammal with a therapeuticallyeffective amount of a composition comprising an X-ray contrast media.The methods further can include, for example, identifying the mammal asa mammal who suffers from a colon inflammatory condition. For example,the condition can be inflammatory bowel disease, irritable bowelsyndrome and the like. In some embodiments, any one or more of the coloninflammatory conditions listed herein can be specifically excluded fromthe methods and compositions.

In some embodiments the composition can be formulated as a rectalformulation. For example as a retention enema. In some aspects, therectal formulation can be formulated to be absorbed, including partiallyor substantially absorbed, by the colon. For example, the retentionenema can be formulated to be substantially absorbed by the colon. Therectal formulations can further include a preservative. The preservativecan include, for example, a quaternary ammonium compound, analkyl-mercury salt of thiosalicylic acid, a paraben, an alcohol, abiguanide derivative, a stabilized oxychloro complex, apolyglycol-polyamine condensation resin, a stabilized hydrogen peroxide,and the like. For example, the preservative can be at least one ofbenzalkonium chloride, benzoxonium chloride, benzethonium chloride,cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphenbromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuricacetate, phenylmercuric borate, methylparaben, propylparaben,chlorobutanol, benzyl alcohol, phenyl ethyl alcohol, chlorohexidine,polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea,sorbic acid, Purite®), Polyquart®), sodium perborate tetrahydrate andthe like. In some embodiments the quaternary ammonium compound can be abenzalkonium chloride, for example trimethyl benzyl ammonium chlorideand the like. In some aspects, one or more of the above-listedingredients can be specifically excluded from some of the compositionsand methods.

Some embodiments relate to methods of treating conditions related toinflammation of the esophagus in a mammal in need thereof, which methodscan include contacting at least part of the esophagus of the mammal witha therapeutically effective amount of a composition comprising an X-raycontrast media. The conditions can be related to inflammation of theesophagus. For example, the condition can be allergic esophagitis,eosinophilic esophatitis, and the like. In some embodiments, any one ormore of the esophageal inflammatory conditions listed herein can bespecifically excluded from the methods and compositions.

In some embodiments the composition can be formulated as an oralformulation. For example, the oral formulations can be a liquid, a gel,a syrup, a slurry and the like. Also, in some aspects, the oralformulation can be a spray formulation, a mouth rinse formulation, amouthwash formulation, a lozenge formulation and the like. The oralformulations can further include a preservative. The preservative caninclude, for example, a quaternary ammonium compound, an alkyl-mercurysalt of thiosalicylic acid, a paraben, an alcohol, a biguanidederivative, a stabilized oxychloro complex, a polyglycol-polyaminecondensation resin, a stabilized hydrogen peroxide, and the like. Forexample, the preservative can be at least one of benzalkonium chloride,benzoxonium chloride, benzethonium chloride, cetrimide, sepazoniumchloride, cetylpyridinium chloride, domiphen bromide (Bradosol®),thiomersal, phenylmercuric nitrate, phenylmercuric acetate,phenylmercuric borate, methylparaben, propylparaben, chlorobutanol,benzyl alcohol, phenyl ethyl alcohol, chlorohexidine, polyhexamethylenebiguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®),Polyquart®), sodium perborate tetrahydrate and the like. In someembodiments the quaternary ammonium compound can be a benzalkoniumchloride, for example trimethyl benzyl ammonium chloride and the like.In some aspects, one or more of the above-listed ingredients can bespecifically excluded from some of the compositions and methods.

In some embodiments, the compositions that include an X-ray contrastmedia can be contacted with the affected area of the mammal with thecomposition on a daily basis. Alternatively, in some embodiments, thecompositions that include an X-ray contrast media can be contacted withthe affected area of the mammal with the composition on an as-neededbasis.

In some embodiments, the X-ray contrast media can be a monomeric,dimeric, nonionic, or ionic compound. Further, in some aspects, theX-ray contrast media can be triiodinated, completely or partiallysubstituted, benzene moieties existing in the form of a monomer or adimer. For example, the X-ray contrast media can be at least one ofIOPAMIDOL, IOVERSOL, IOPROMIDE, IOHEXOL, IOTHALAMATE, DIATRIZOATE,IOXAGLATE, IODIPAMIDE, IODIXANOL, IOTROLAN, IOPANOIC ACID, TYROPANOATE(e.g., Na tyropanoate (BILOPAQUE)), and the like. In some aspects of themethods and compositions described herein, any one or more of the listedcontrast media can be specifically excluded.

Some embodiments relate to methods of treating a common cold in a mammalin need thereof, which methods can include administering atherapeutically effective amount of a composition that includes an X-raycontrast media. The methods further can include, for example,identifying the mammal as a mammal that suffers from a common cold. Insome aspects, treatment of the common cold can include treating asymptom of the common cold. For example, the symptom of the common coldcan be a stuffy nose or nasal congestion. Also, in one aspect, thetreatment of the common cold does not result in a rebound effect. Insome embodiments, the therapeutically effective amount of a compositionthat includes an X-ray contrast media can be administered as an aerosolformulation. In some embodiments, any one or more of the common coldsymptoms or conditions listed herein can be specifically excluded fromthe methods and compositions.

Some embodiments relate to methods of preparing a composition fortreatment of an inflammatory condition or a common cold, which caninclude contacting an X-ray contrast media with a preservative. Thepreservative can be at least one of benzalkonium chloride, benzoxoniumchloride, benzethonium chloride, cetrimide, sepazonium chloride,cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal,phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate,methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenylethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodiumperborate, imidazolidinyl urea, sorbic acid, Purite®), Polyquart®),sodium perborate tetrahydrate and the like. In some aspects, the X-raycontrast media can mixed with the preservative. In some aspects, one ormore of the above-listed ingredients can be specifically excluded fromsome of the compositions and methods. Also, in some aspects the X-raycontrast media and the preservative can be stored in a container. Forexample, the container can be a spray bottle, a container with a lid andthe like.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of the arm of a human showing the response toinjected histamine, dust antigen and grass antigen both with and withoutpre-treatment with iodipamide.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Embodiments disclosed herein relate to the unexpected discovery thatX-ray contrast media can be used to treat various inflammatoryconditions, including for example, those of the common cold. In someembodiments, the invention relates to methods of treating a conditionrelated to inflammation of the upper respiratory track or bronchi,including the common cold, the skin, the esophagus, and the colon.

Specifically, some embodiments to methods of treating one of theseconditions by applying an X-ray contrast media in a manner to contactone or more of the respective inflamed cells or parts of theaforementioned regions. In other embodiments, the invention relates tocompositions comprising X-ray contrast media formulated to contactinflamed regions or cells of the skin, upper respiratory track orbronchi, colon, or the esophagus. Also, some embodiments relate to theuse of X-ray contrast media to treat the common cold. Specifically, someembodiments relate to compositions, including a topical composition, anaerosolized composition, an enema composition, or an oral compositioncomprising an X-ray contrast media. In some aspects, any one or more ofthe contrast media can be specifically excluded in the methods andcompositions described herein.

X-ray contrast media (CM) can be used to treat and provide relief ofsymptoms in the spectrum of inflammatory and hypersensitivity conditionsthat include conditions of the skin, esophagus, colon, bronchi/upperrespiratory tract, certain neoplasms, and the common cold. Many of theseconditions are associated with the activity of mast cells. Thetriggering of mast cells leads to degranulation and the release ofpreformed mediators. Surprisingly, CM can inhibit mast cell activation.It is not believed that any other drugs have a similar totipotentialcapacity as seen with CM. This potential permits the contrast media tobe applied in a number of ways that permit inhibition of mast cells.These cells, when activated, are increasingly recognized to participatein a large number of inflammatory conditions. Furthermore, CM canfunction as general enzyme inhibitors, including at concentrationsattainable with topical application. Also, CM can act as effectiveinhibitors of various enzymes, including against adenosine triphosphate,carbonic anhydrase, and angiotensin converting enzyme, alcoholdehydrogenase, and beta-glucuronidase, even at topical concentrations.These attributes permit the CM to function as potent anti-inflammatoriesand to be effective at treating or minimizing various disease conditionsand neoplasms.

X-ray Contrast Media

X-ray contrast media have been used for many years in the field ofradiology. While the molecules have assumed some structural differencesover the years, the basic concept that iodine attached to organic ringstructures will impair x-ray penetration remains the same. The x-raymolecules, referred to as “contrast media” have been used to opacifyblood vessels, organs, and other parts of the body that have orificesleading externally or are amenable to needle injection.

X-ray contrast media today are generally triiodinated, completely orincompletely substituted, benzene moieties existing in the form of amonomer or a dimer. These contrast media molecules can be either ionicor nonionic (or in the case of one dimer, part ionic and part nonionic).Generally, there can be slight variations in the amide side chainsattached at the 3 and 5 positions on the ring and in the nature of thecations (for the ionic media) and there can be slight differences in thelength of the aliphatic chains linking the dimers and in the nature ofthe coupler group.

Some examples of X-ray contrast media that are commercially availabletoday are iopadmidol, ioversol, iopromide, and iohexyl which arenonionic monomers. Iothalamate and diatrizoate are ionic monomers.Ioxoglate and iodipamide are ionic dimers, while iodixanol and iotrolanare nonionic dimers.

Surprisingly, X-ray contrast media have now been discovered as disclosedherein to be useful for treating inflammatory conditions of the skin,the bronchi, the esophagus and the colon. Any X-ray contrast media canbe used in the methods and compositions described herein, including forexample, iopamidol, ioversol, iopromide, iohexyl, iothalamate,diatrizoate, ioxaglate, iodipamide, iodixanol, iopanoic acid, sodiumtyropanoate (BILOPAQUE) and iotrolan. Any one of the contrast mediadescribed herein can be specifically excluded from the methods andcompositions described herein.

Patient Identification

Compositions described herein can be administered to a subjectexperiencing or at risk of experiencing a condition related toinflammation and/or related to the common cold. The patient subject canbe selected from a variety of mammals including mice; rats; rabbits;guinea pigs; dogs; cats; sheep; goats; cows; horses; pigs; primates,such as monkeys, chimpanzees, and apes; and humans.

In some embodiments, the patient can be one who has never experienced aninflammatory reaction. In other embodiments, the patient can haveexperienced at least one or more inflammatory reactions. The patient canalso experience inflammatory reactions that may or may not be triggeredby known allergens. In some embodiments, the inflammatory reaction canbe a reaction to a skin allergen, such as a cleaning solution, adetergent, a cosmetic, a soap or shampoo, a medication, a sun block, alotion, a perfume, an industrial chemical, a latex rubber, a dustallergen, a grass allergen, a cat allergen or a component therein, orthe skin allergen can be poison ivy, poison oak, or poison sumac. Insome embodiments, one or more of the allergens can be excluded from themethods described herein.

In some embodiments, patients can be identified for the methodsdescribed herein by the observation of symptoms related to inflammation.In other embodiments, patients can be predisposed to a condition relatedto inflammation, for example, due to a genetic predisposition or due tothe occurrence of a related condition. In still other embodiments,clinical tests, such as allergy tests, can identify patients for themethods described herein.

In some embodiments, a patient can have or be at risk of having a cold.The cold may be a common cold produced by a number of different viruses.The cold may include nasal symptoms, such as a runny nose, nasalcongestion or cough.

Furthermore, in some embodiments, the patient may be suffering from orat risk for a condition related to immune cell activation due to theconversion of angiotensin-I to angiotensin-II. In some aspects thecontrast media can be used to inhibit the conversion, thereby reducingthe immune cell activation that can lead to inflammation.

Methods and Compositions

In some embodiments, methods herein relate to methods of treating apatient suffering from or at risk of suffering from a condition which isrelated to inflammation. In some embodiments, the condition related toinflammation can be attributable to hyperactivity of an immune cell. Inother embodiments, multiple types of immune cells may be hyperactive. Instill other embodiments, the invention relates to compositionsspecifically formulated to treat specific immune cells or immune cellslocated in particular regions of the body. In some embodiments, thecontrast media can include one or more of the contrast media describedherein. In some aspects of the embodiments, one or more of the contrastmedia described herein can be excluded. In some embodiments, any one ofthe specific indications described below can be specifically excluded.

Skin Immune Cells and Skin Inflammatory Conditions

Certain immune cells of the skin may differ in their morphology,histochemical properties, and functional properties from other immunecells. Additionally, immune cells of the skin may be deep in the tissuecompared to other immune cells. Surprisingly, some embodiments are basedupon the surprising discovery that contrast media can have efficacyagainst skin inflammatory conditions.

Some embodiments relate to compositions comprising an X-ray contrastmedia that can be used to treat or inhibit inflammatory conditions ofthe skin. In some embodiments, the compositions can include a topicalcarrier such as an emollient and an X-ray contrast media that can beused to treat inflammatory conditions of the skin. The topical carriercan increase the percutaneous absorption of the composition. Althoughany CM can be used, in some preferred aspects, lipophilic CM such as theionic dimer iodipamide can be used. Emollients can be used to furtherimprove absorption and penetration of the CM. For example, iodixanol, ahydrophilic CM, can be formulated with an excipient/emollient in orderto improve skin absorption. In some aspects of the methods for treatmentor inhibition of inflammatory conditions of the skin, one or more of theCM described herein can be specifically excluded.

In some embodiments, methods described herein can be used to treatconditions related to inflammation. These conditions can include eczema,dermatitis, dermatosis, inflammation caused by graft v. host disease,inflammation caused by immunobullous disease, an insect bite reaction, asunburn or a skin allergen reaction. The skin allergen can be, forexample, a shampoo or perfume or a component therein or the skinallergen can be latex, poison ivy, poison oak, poison sumac, a dustallergen, a grass allergen, or a pet allergen, e.g. a cat allergen orthe like. The dermatosis can be psoriasis or atopic dermatitis. In someembodiments, any one or more of the skin inflammatory conditions listedherein can be specifically excluded from the methods and compositions.

Also, the injection of an allergen or vaccine can provoke a hyperimmune(anaphylactic) reaction. Some embodiments relate to concomitantintradermal or subdermal injections CM in sufficient concentrations atthe site of the concomitant injection in order to reduce or prevent thehyperimmune reaction. In some embodiments, any one or more of the skininflammatory conditions listed herein can be specifically excluded fromthe methods and compositions.

The inhibitory effects of X-ray contrast materials (CM) on mast cellsand the array of immune cells permits CM to have efficacy in a widevariety of inflammatory skin conditions. In addition to atopicdermatitis, several other pruritic skin conditions including prurigonodularis, papular urticaria, and pruritis vulvae can be treated withCM. Also, CM can be used to treat allergic contact dermatitis, latexallergy, and irritant contact dermatitis. Mast cells, in part byelaboration of tumor necrosis factor (TNF), contribute to the expressionof certain models of contact hypersensitivity. See Suto H, Nakae S,Kakurai M, Sedgwick J D, Tsai M, Galli S J. Mast cell associated TNFpromotes dendritic cell migration. J. Immunol. 2006 Apr. 1; 176(7):4102-12, which is incorporated herein by reference in its entirety, inparticular (without being limited thereto), for the inflammatoryconditions or mechanisms that can be minimized or treated with CM.

In psoriasis, known mediators of inflammation include dendritic cells,Langerhans cells, T-lymphocytes, and mast cells, which are thought to bea primary source of TNF that is overexpressed and important in thepathophysiology of the disease (Kawaguchi M, Mitsuhashi Y, Kondo S.Overexpression of tumor necrosis factor-alpha-converting enzyme inpsoriasis. Br J Dermatol. 2005 May; 152(5): 915-9, which is incorporatedherein by reference in its entirety, in particular (without beinglimited thereto), for the inflammatory conditions or mechanisms that canbe minimized or treated with CM). Other similar papulo-squamousdermatoses including pityriasis rosea and lichen planus can be treatedwith topical CM.

CM can be used to treat sclerosing dermatoses, including scleroderma,morphea, and lichen sclerosis. Sclerosing dermatoses, includingscleroderma, morphea, and lichen sclerosis are characterized byincreased dermal collagen, thought to be related to increased mast cellsand histamine effects (Falanga V, Soter N A, Altman R D, Kerdal F A.Elevated plasma histamine levels in systemic sclerosis (Scleroderma).Arch Dermatol. 1990 March; 126(3):336-8; which is incorporated herein byreference in its entirety, in particular (without being limitedthereto), for the inflammatory conditions or mechanisms that can beminimized or treated with CM), and are candidates for application oftopical CM therapy.

Bronchial Immune Cells and Bronchial Inflammatory Conditions

Certain bronchial immune cells can differ from other immune cells bycloser proximity to the airway. Bronchial immune cells can also differfrom other immune cells by the types of mediators they release. Thedensity of bronchial immune cells can be higher than other immune cells.The results of immune cell release in the bronchii can includebronchospasm and mucus production. Surprisingly, contrast media cancontact the cells of the bronchii and come into proximity with immunecells involved in an inflammatory condition.

Some embodiments relate to compositions comprising an X-ray contrastmedia that can be used to treat or inhibit inflammatory conditions ofthe bronchii. In some embodiments, the compositions can include acarrier and an X-ray contrast media. The carrier can affect thesolubility and/or the diffusivity of the composition compared to thesolubility and/or the diffusivity of the X-ray contrast media. Someother embodiments relate to aerosolized compositions comprising an X-raycontrast media. The aerosolized compositions can provide a mechanism ofobtaining a high surface area of contact between the composition and theupper airway system. In other embodiments, the formulation can be aninhaled powder cut in such a fashion that it will be predisposed to coatthe bronchi rather than areas higher or lower in the respiratory systemand will not be itself an irritant.

Accordingly, some embodiments relate to methods and compositions totreat a conditions resulting from bronchial immune cell hyperactivity orrelated to a bronchial inflammatory condition. The condition can be, forexample, asthma, bronchitis including allergic or asthmatic bronchitis,or bronchoconstriction. In some aspects, any one of the contrast mediadescribed herein can be specifically excluded from the methods andcompositions. Also, in some embodiments, any one or more of thebronchi/respiratory inflammatory conditions listed herein can bespecifically excluded from the methods and compositions.

Colon Immune Cells and Colon Inflammatory Conditions

Certain colon immune cells can differ from other immune cells. Colonimmune cells can be located in the epithelial or subepithelial layers ofthe colon, Surprisingly, contrast media given in a retention enema canpermeate epithelial cells and can also gain entrance to theintercellular space giving proximity to the immune cells.

Some embodiments relate to compositions comprising an X-ray contrastmedia that can be used to treat or inhibit inflammatory conditions ofthe colon. In some embodiments, the compositions can include an enemacomposition comprising an X-ray contrast media. The composition can alsocomprise a carrier. The carrier can affect the solubility and/or thediffusivity of the composition compared to the solubility and/or thediffusivity of the X-ray contrast media. The carrier can also comprise asuspending or thickening agent to prolong release of the X-ray contrastmedia.

Accordingly, some embodiments relate to methods and compositions totreat a condition related to colon immune cell hyperactivity or relatedto a colon inflammatory condition. These conditions can include, forexample, inflammatory bowel disease, irritable bowel syndrome, andulcerative colitis. In some aspects, any one of the contrast mediadescribed herein can be specifically excluded from the methods andcompositions. Also, in some embodiments, any one or more of the coloninflammatory conditions listed herein can be specifically excluded fromthe methods and compositions.

Esophageal Immune Cells and Esophageal Inflammatory Conditions

Certain esophageal immune cells can differ from other immune cells.Esophageal immune cells can be located in the lamina propria, the deepsubmucosa, and/or the muscularis propria of the esophagus. Surprisingly,some embodiments relate to the surprising discovery that X-ray contrastmedia can treat inflammatory conditions of the esophagus.

Some embodiments relate to compositions comprising an X-ray contrastmedia that can be used to treat or inhibit inflammatory conditions ofthe esophagus. In some embodiments, the compositions can include oralcompositions comprising an X-ray contrast media. The oral compositioncan include, for example, a carrier that improves the absorption of thecomposition through the esophagus, for example, as compared to theabsorption of the certain X-ray contrast media alone. The oralcomposition can also include a thickener that prolongs the transit ofthe contrast media through the esophagus, for example.

Accordingly, some embodiments relate to compositions and methods thatcan be used to treat a condition related to esophagus immune cellhyperactivity or related to an esophageal inflammatory condition. Thecondition can be, for example, esophagitis including allergicesophagitis. In some aspects, any one of the contrast media describedherein can be specifically excluded from the methods and compositions.Also, in some embodiments, any one or more of the esophagealinflammatory conditions listed herein can be specifically excluded fromthe methods and compositions

Common Cold

Common colds can include a variety of symptoms, including ablocked/stuffy nose, a runny nose, and a cough. Many cold medicinescurrently marketed to relieve a blocked nose comprise ephedrine. Suchmedications can be associated with a “rebound effect.” A rebound effectcan occur by overusing a nasal spray decongestant such that the bloodvessels in the nose swell, resulting in worsened symptoms. Meanwhile,other treatments, such as corticosteroids, antihistamines andcromoglycates, appear incompletely effective in relieving the blockednose symptom. Further, common cold medicines can be associated with sideeffects, such as drowsiness and nasal irritation. Surprisingly, someembodiments relate to the surprising discovery that X-ray contrast mediacan treat cold symptoms, including inflammatory conditions associatedwith the common cold.

Some embodiments relate to compositions comprising an X-ray contrastmedia that can be used to treat the common cold or a symptom of thecommon cold, such as a stuffy nose. The composition for example canrelieve or partially relieve a symptom of the cold. The composition canreduce the duration of the cold. In some aspects, any one of thecontrast media described herein can be specifically excluded from themethods and compositions. Also, in some embodiments, any one or more ofthe cold conditions or symptoms listed herein can be specificallyexcluded from the methods and compositions

Though not wishing to be bound by any particular theory, it is likelythat the mechanism of action involves inhibition of angiotensinconverting enzyme (ACE), inhibition of mast cell activity, generalenzyme inhibitory effects, and antihistaminic effects. Ace isresponsible for the conversion of angiotensin I to angiotensin II, thelatter of which is an activator of the innate immune response expressedby activated macrophages and T-cells, Immune cells, includingmacrophages, T-cells and B-cells and neutrophils, contain receptors forangiotensin 2. Viral-induced activation of these cells in the nasalsubmucosa can produce some of the mediators responsible for the symptomsof the “cold.” Some embodiments relate to methods of inhibitingangiotensin converting enzyme, for example, in a patient suffering fromor susceptible to a condition described herein or any other conditioncaused by or contributed to by the conversion of angiotensin I toangiotensin II. The methods can include the identification of such apatient.

Treatment of Neoplasms and Other Conditions

Some embodiments relate to the use of X-ray contrast materials for thetreatment of neoplasms or cancers, in particular those cancers orneoplasms where mast cells contribute to the disease condition andprogression.

The inhibition of angiogenic molecules from mast cells includingangiopoietin, heparin, interleukin-8, and vascular endothelial growthfactor can promote cancer cell death. Angiogenesis can play a role inhuman lymphoproliferative disease, including cutaneous T-cell lymphomaand mycosis fungoides (Mazur, G). The latter is a slowly progressiveskin based lymphoma which, at least initially, is treated by skin basedtherapies. Some embodiments relate to topical application of contrastmedia to inhibit the inflammatory and angiogenic process that supportscutaneous lymphoma progression. Thus topical application of CM canimpede tumor growth of several different kinds. See Mazur, G et al,Pathol Oncol Res. 2004; 10(1): 34-36 Epub 2004 Mar. 18, which isincorporated herein by reference in its entirety, and particularlyincorporated for several examples of disease conditions that can betreated using CM.

Some embodiments relate to the use of X-ray contrast materials for thetreatment of pancreatic neoplasms, such as pancreatic ductaladenocarcinomas. The release of some substances from activated mastcells may play a role in the production of pancreatic ductaladenocarcinomas. For example, the mast cells may contribute toangiogenesis or macroscopic expansion of pancreatic islet tumors.Surprisingly, X-ray contrast media can inhibit activation of mast cellsin pancreatic tissue. Thus, in some aspects, one or more X-ray contrastmaterials can be contacted with the pancreatic duct, for example, via acatheter or by injection to inhibit the mast cells and thereby inhibitthe growth of pancreatic carcinomas. For example, the pancreatic cellscan be washed over by the CM in order to treat the pancreaticadenocarcinoma. Again, the CM can be administered by any route or meansthat permits contact of the CM with the cells. Preferably, the CM can beadministered via catheter, via intraperitoneal injection or by suffusingthe pancreas via injections into the arterial system leading thepancreas.

Route of Administration and Formulation

The exact formulation and route of administration for the compositionsdescribed herein can be chosen by the individual physician in view ofthe patient's condition. See e.g., Fingl et al. 1975, in “ThePharmacological Basis of Therapeutics,” Ch. 1 p. 1; which isincorporated herein by reference in its entirety. As set forth morefully below, preferred routes of administration include, for example,topical, oral, rectal, parenteral delivery (including intramuscular,subcutaneous, injections), as well as, intranasal, or ocular injections.As mentioned above, U.S. Provisional Application Ser. No. 60/914,642,filed on Apr. 27, 2007, and U.S. Provisional Application Ser. No.60/981,093, filed on Nov. 28, 2007 by Elliott C. Lasser and bothentitled “COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATORYCONDITIONS,” are each incorporated herein by reference in theirentirety. In particular, the appendix to the specification (Remington'sPharmaceutical Sciences) is incorporated herein for all of the variousformulations, ingredients, excipients, etc., listed therein. The variousX-ray contrast materials listed herein, alone or in combination, can beincorporated into or used with the materials described in Remington's.

Alternately, one can administer the compound in a local rather thansystemic manner, for example, via direct application to the skin orregion of interest for treating, including using a depot or sustainedrelease formulation. Furthermore, one can administer the drug in atargeted drug delivery system, for example, in a liposome coated with atissue-specific antibody. The liposomes will be targeted to and taken upselectively by the organ or cells of the desired region.

In some embodiments, the contrast media can be administered alone. Inother embodiments, the contrast media can be administered in combinationwith one or more additional materials, for example, as two separatecompositions or as a single composition where the additional material(s)is (are) mixed or formulated together with the contrast media. Forexample, without being limited thereto, the contrast media can beformulated with additional excipients, additional active ingredients,other contrast media. In some aspects, when administered in the formsdescribed herein the contrast media can attain concentrations at atarget tissue such as the nose, the eye, the bronchi, the skin, etc.that cannot be attained by the usual intravascular administration of thecontrast material.

The pharmaceutical compositions can be manufactured by any suitablemanner, including, e.g., by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or tableting processes.

Pharmaceutical compositions for use in accordance with the inventionthus can be formulated in any suitable manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation candepend upon the route of administration chosen. Any suitable techniques,carriers, and excipients can be used, including those understood in theart; e.g., in Remington's Pharmaceutical Sciences, above. The attachedpages 1523-1553 from Remington's Pharmaceutical Sciences areincorporated herein by reference in their entirety.

Topical Formulations

Compositions comprising an X-ray contrast media can be, in someembodiments, topical compositions. The topical composition can beformulated such that the X-ray contrast media is absorbed, includingsubstantially absorbed, percutaneously. The topical composition can beformulated to increase the probability that the X-ray contrast media ofthe composition will contact inflamed tissues and immune cells. Thecomposition can comprise a carrier. The carrier can improve theabsorption of the composition as compared to the absorption of the X-raycontrast media alone. The composition can include, for example, apenetration enhancing agent such as dimethylsulfoxide, propylene glycol,AZONE™, and the like.

Carriers are further described below. However, in some embodiments, thecarrier can be selected from castor oil, ethylene glycol, monobutylether, diethylene glycol monoethyl ether, corn oil, dimethyl sulfoxide,ethylene glycol, isopropanol, soybean oil, glycerin, zinc oxide,titanium dioxide, glycerin, butylene glycol, cetyl alcohol, and sodiumhyaluronate.

The topical formulation can be the contrast media alone, or the contrastmedia in combination with a gel, a cream, a lotion, a paste, anointment, an oil, or a foam. The topical composition can be combinedwith other topical compositions, such as shampoo. Additionally, amultitude of appropriate topical compositions can be utilized. See e.g.,Blaug, in “Remington's Pharmaceutical Sciences” Mack publishing Company,Easton Pa., 15th edition, 1975, Ch. 87 which is incorporated herein byreference in its entirety. These compositions include, for example,powders, pastes, ointments, jelly, waxes, oils, lipids, anhydrousabsorption bases, oil-in water or water-in-oil emulsions, emulsionscarbowax (polyethylene glycols of a variety of molecular weights),semi-solid gels, semi-solid mixtures containing carbowax, and the like.

Aerosolized Formulations

Compositions comprising an X-ray contrast media can be, in someembodiments, aerosolized compositions. The aerosolized composition canbe formulated such that the composition has increased solubility and/ordiffusivity. The aerosolized composition can be formulated to increasethe probability that the X-ray contrast media of the composition willcontact bronchial inflammation and/or immune cells. The composition cancomprise a carrier. The carrier can improve the absorption of thecomposition, change the viscosity of the composition, change thesolubility of the composition, or change the diffusivity of thecomposition as compared to that of the X-ray contrast media alone.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. an X-ray contrast media asdefined above and optional pharmaceutical adjuvants in a carrier (e.g.,water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like)to form a solution or suspension. Solutions to be aerosolized can beprepared in any suitable form, for example, either as liquid solutionsor suspensions, as emulsions, or in solid forms suitable for dissolutionor suspension in liquid prior to aerosol production and inhalation.

For administration by inhalation, the compositions described herein canconveniently be delivered in the form of an aerosol (e.g., throughliquid nebulization, dry powder dispersion or meter-dose administrationThe aerosol can be delivered from pressurized packs or a nebulizer, withthe use of a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitcan be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator can be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

By non-limiting example water-based liquid formulations can include anX-ray contrast media alone or with non-encapsulating water solubleexcipients. Simple formulations can also include organic-based liquidformulations for nebulization or meter-dose inhaler. By non-limitingexample organic-based liquid formulations can include an X-ray contrastmedia or with non-encapsulating organic soluble excipients.

Simple formulations can also include dry powder formulations foradministration with a dry powder inhaler. By non-limiting example drypowder formulations can include an X-ray contrast media alone or witheither water soluble or organic soluble non-encapsulating excipientswith or without a blending agent such as lactose.

Formulations can include water-based liquid formulations fornebulization. A non-limiting example water-based liquid complexformulations can include X-ray contrast media encapsulated or complexedwith water-soluble excipients such as lipids, liposomes, cyclodextrins,microencapsulations, and emulsions.

Formulations can also include organic-based liquid formulations fornebulization or meter-dose inhaler. A non-limiting example organic-basedliquid complex formulations can include X-ray contrast mediaencapsulated or complexed with organic-soluble excipients such aslipids, microencapsulations, and reverse-phase water-based emulsions.

Formulations can also include low-solubility, water-based liquidformulations for nebulization. A non-limiting example low-solubility,water-based liquid complex formulations can include X-ray contrast mediaas a low-water soluble, stable nanosuspension alone or inco-crystal/co-precipitate excipient complexes, or mixtures with lowsolubility lipids, such as lipid nanosuspensions.

Formulations can also include low-solubility, organic-based liquidformulations for nebulization or meter-dose inhaler. A non-limitingexample low-solubility, organic-based liquid complex formulations caninclude X-ray contrast media as a low-organic soluble, stablenanosuspension alone or in co-crystal/co-precipitate excipientcomplexes, or mixtures with low solubility lipids, such as lipidnanosuspensions.

Formulations can also include dry powder formulations for administrationusing a dry powder inhaler. A non-limiting example, complex dry powderformulations can include X-ray contrast media inco-crystal/co-precipitate/spray dried complex or mixture with low-watersoluble excipients/salts in dry powder form with or without a blendingagent such as lactose.

Specific methods for simple and complex formulation preparation aredescribed herein. Any suitable X-ray contrast media, including thosedescribed herein, are preferably directly administered as an aerosol tothe respiratory tract.

Any suitable device technology can be used to deliver, for example, adry powder or a liquid aerosolized product comprising an X-ray contrastmaterial. Dry powder formulations in some circumstances can require lesstime for drug administration. Liquid formulations can have longeradministration times.

For aqueous and other non-pressurized liquid systems, a variety ofnebulizers (including small volume nebulizers) can be used to aerosolizethe formulations. Compressor-driven nebulizers can utilize jettechnology and can use compressed air to generate the liquid aerosol.Such devices are commercially available from, for example, HealthdyneTechnologies, Inc.; Invacare, Inc.; Mountain Medical Equipment, Inc.;Pari Respiratory, Inc.; Mada Medical, Inc.; Puritan-Bennet; Schuco,Inc., DeVilbiss Health Care, Inc.; and Hospitak, Inc. Ultrasonicnebulizers generally rely on mechanical energy in the form of vibrationof a piezoelectric crystal to generate respirable liquid droplets andare commercially available from, for example, Omron Heathcare, Inc. andDeVilbiss Health Care, Inc. Vibrating mesh nebulizers rely upon eitherpiezoelectric or mechanical pulses to respirable liquid dropletsgenerate Commercial examples of nebulizers that Respirgard II®,Aeroneb®, Aeroneb® Pro, and Aeroneb® Go produced by Aerogen; AERx® andAERx Essence™ produced by Aradigm; Porta-Neb®, Freeway Freedom™,Sidestream, Ventstream and I-neb produced by Respironics, Inc.; and PARILC-Plus®, PARI LC-Star®, and e-Flow7m produced by PARI, GmbH. By furthernon-limiting example, U.S. Pat. No. 6,196,219, is hereby incorporated byreference in its entirety.

In some embodiments, the drug solution can be formed prior to use of thenebulizer by a patient. In other embodiments, the drug can be stored inthe nebulizer in solid form. In this case, the solution can be mixedupon activation of the nebulizer, such as described in U.S. Pat. No.6,427,682 and PCT Publication No. WO 03/035030, both of which are herebyincorporated by reference in their entirety. In these nebulizers, thedrug, optionally combined with excipients to form a solid composition,can be stored in a separate compartment from a liquid solvent

Enema Formulations

Compositions comprising an X-ray contrast media can be, in someembodiments, enema compositions. The enema composition can be formulatedsuch that the composition has different solubility and/or diffusivitythan the X-ray contrast media alone. The enema composition can beformulated to increase the probability that the X-ray contrast media ofthe composition will contact colon inflammatory condition and/or immunecells. The composition can comprise a carrier. The carrier can improvethe absorption of the composition, change the viscosity of thecomposition, change the solubility of the composition, or change thediffusivity of the composition as compared to that of the X-ray contrastmedia alone.

The compositions can also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing suitable suppositorybases such as cocoa butter or other glycerides. Retention enemapreparations or solutions for rectal or colonic irrigation can be theactive ingredient alone or can be made by combining the activeingredient with a pharmaceutically acceptable liquid carrier. Thecarrier vehicle can be a natural or synthetic thickener such as gums,acrylates or modified celluloses. The formulation can also comprise aneffective amount of a lubricant such as a natural or synthetic fat oroil, e.g. a tris-fatty acid glycerate or lecithin. Nontoxic nonionicsurfactants can also be included as wetting agents and dispersants. Unitdosages of enema formulations can be administered from prefilled bags orsyringes. The carrier vehicle can also comprise an effective amount of afoaming agent such as n-butane, propane or i-butane. Such formulationscan be delivered from a preloaded syringe pressurized container, so thatthe vehicle is delivered to the colon as a foam, which inhibits itsescape from the target site. As is well known in the art, enemapreparations can be administered using, and can be packaged within, adelivery device adapted to the rectal anatomy of the subject.

Oral Formulations

Compositions comprising an X-ray contrast media can be, in someembodiments, oral compositions. The oral composition can be formulatedsuch that the composition has different solubility and/or diffusivitythan the X-ray contrast media alone. The oral composition can beformulated to increase the probability that the X-ray contrast media ofthe composition will contact esophageal inflammatory conditions and/orimmune cells. The composition can comprise a carrier. The carrier canchange the absorption of the composition, change the viscosity of thecomposition, change the solubility of the composition, or change thediffusivity of the composition as compared to that of the X-ray contrastmedia.

In some aspects, the X-ray contrast media can be used alone or can beformulated readily by combining the active compounds withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the contrast media to be formulated as liquids, gels,syrups, slurries, suspensions and the like, for oral ingestion by apatient to be treated. In some embodiments, oral compositions can beformulated as a spray, a mouth rinse, a mouthwash, and a lozenge are, inparticular, fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; cellulose preparations such as, for example,maize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents can be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

The compositions described herein can be included in a food or beverageproduct. In some preferred embodiments, the compositions can be includedin a food or beverage product similar to the craved substance. The foodor beverage product can be a beverage, a soup, a solid, a semi-solid, ora frozen confection. The beverage can be a still beverage or acarbonated beverage, and moreover, can be a suspension, for example, ashake, frappe, or float. Both carbonated and non-carbonated beveragescan be “diet” beverages made with low calorie or no-calorie sweeteners,including saccharine, aspartame, dihydrochalcones, monellin,steviosides, glycyrrhizin, sorbitol, mannitol, maltitol, and others. Thebeverage can be an infusion or extract including a tea or a coffee. Thecontrast media can also be in a powder form. Preferably the powder isfree-flowing and readily mixable with water or other fluid. The powdercan be mixed with a variety of fluids. Thus, for example, the powderform can be mixed with water, soda, diet soda, tea, coffee, fruit juice,diet fruit juice, flavored diet beverages, and the like. Preferably, thepowder form can be mixed with water or other fluid before drinking. Insome embodiments, the contrast media can be delivered in the form of atoothpaste.

The compositions described herein can be formulated as a solutionpreconcentrate; i.e., a composition intended to be dispersed with water,either prior to administration in the form of a drink, or dispersed invivo. The composition can be provided in the form of a dilutedpreconcentrate (i.e., an aqueous dispersion), a semi-solid dispersion ora solid dispersion.

For transmucosal administration, penetrants appropriate to the barrierto be permeated can be used in the formulation. Such penetrants aregenerally known in the art.

For intradermal or subdermal injections standard needle and syringetechniques can be used

Pharmaceutical Carriers

The term “carrier” defines a chemical compound that facilitates theincorporation of a compound into cells or tissues. For example dimethylsulfoxide (DMSO) is a commonly utilized carrier as it facilitates theuptake of many organic compounds into the cells or tissues of anorganism. In some embodiments, a pharmaceutical carrier for acomposition described herein can be selected from castor oil, ethyleneglycol, monobutyl ether, diethylene glycol monoethyl ether, corn oil,dimethyl sulfoxide, ethylene glycol, isopropanol, soybean oil, glycerin,zinc oxide, titanium dioxide, glycerin, butylene glycol, cetyl alcohol,and sodium hyaluronate.

A pharmaceutical carrier for the hydrophobic compounds of the inventionis a cosolvent system comprising benzyl alcohol, a nonpolar surfactant,a water-miscible organic polymer, and an aqueous phase. A commoncosolvent system used is the VPD co-solvent system, which is a solutionof 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate80™, and 65% w/v polyethylene glycol 300, made up to volume in absoluteethanol. Naturally, the proportions of a co-solvent system can be variedconsiderably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentscan be varied: for example, other low-toxicity nonpolar surfactants canbe used instead of POLYSORBATE 80™; the fraction size of polyethyleneglycol can be varied; other biocompatible polymers can replacepolyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars orpolysaccharides can substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds can be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as dimethylsulfoxide also can be employed,although usually at the cost of greater toxicity. Additionally, thecompounds can be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. The pharmaceutical compositions described herein canbe administered to a patient per se, or in pharmaceutical compositionswhere they are mixed with other active ingredients, as in combinationtherapy, or suitable carriers or excipient(s). The compounds andcompositions can be formulated with salts or excipients, such as forexample, sodium or meglumine. Techniques for formulation andadministration of the compounds of the instant application can be foundin “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton,Pa., 18th edition, 1990.

Furthermore, the compounds and compositions used herein can preferablybe stable over an extended period of time, for example on the order ofmonths or years. Compositions comprising an X-ray contrast media can, insome embodiments, comprise a preservative. The preservative can comprisea quaternary ammonium compound, such as benzalkonium chloride,benzoxonium chloride, benzethonium chloride, cetrimide, sepazoniumchloride, cetylpyridinium chloride, or domiphen bromide (Bradosol®).).The preservative can comprise an alkyl-mercury salt of thiosalicylicacid, such as thiomersal, phenylmercuric nitrate, phenylmercuric acetateor phenylmercuric borate. The preservative can comprise a parabens, suchas methylparaben or propylparaben. The preservative can comprise analcohol, such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol.The preservative can comprise a biguanide derivative, such aschlorohexidine or polyhexamethylene biguanide. The preservative cancomprise sodium perborate, imidazolidinyl urea, and/or sorbic acid. Thepreservative can comprise stabilized oxychloro complexes, such as knownand commercially available under the trade name Purite®). Thepreservative can comprise polyglycol-polyamine condensation resins, suchas known and commercially available under the trade name Polyquart®)from Henkel KGaA. The preservative can comprise stabilized hydrogenperoxide generated from a source of hydrogen peroxide for providing aneffective trace amount of resultant hydrogen peroxide, such as sodiumperborate tetrahydrate. The preservative can be benzalkonium chloride.

The preservative can enable a composition comprising an X-ray contrastmedia to be used on multiple occasions. The preservative can reduce theeffects of one or more of acid exposure, base exposure, air exposure,heat, and light on the X-ray contrast media. The compounds andcompositions used herein can include any suitable buffers, such as forexample, sodium citrate buffer and/or sequestering agents, such asedetate disodium sequestering agent. Ingredients, such as meglumine, maybe added to adjust the pH of a composition or compound described herein.Compounds and compositions described herein may comprise sodium and/oriodine, such as organically bound iodine. Compositions and compoundsused herein may be provided in a container in which the air is replacedby another substance, such as nitrogen.

Dosages

Pharmaceutical compositions suitable for use in the invention includecompositions where the active ingredients are contained in an amounteffective to achieve its intended purpose. A “therapeutically effectiveamount” means an amount to treat or inhibit a symptom related to thespecific inflammatory condition or related to the particular immune cellhyperactivity. The symptom can be a symptom already occurring orexpected to occur. In some embodiments, the symptom can be inflammation,swelling or redness. In some embodiments, the symptom is erythema andswelling that is provoked by an allergen, such as a skin allergen.Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

In other embodiments, a therapeutically effective amount can describethe amount necessary for a significant quantity of the composition tocontact the desired region or immune cells.

Within certain embodiments of the invention, dosages of administeredcontrast media can be from 0.01-0.1 grams, 0.1-5 grams, 5-10 grams,10-15 grams, 15-20 grams, 20-25 grams, 25-30 grams, 30-35 grams, 35-40grains, 40-45 grams, 45-50 grams and 50-200 grams.

The compositions can, if desired, be presented in a pack or dispenserdevice which can contain one or more unit dosage forms containing theactive ingredient. The pack can for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device can beaccompanied by instructions for administration. The pack or dispensercan also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, can be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions comprising a compound of theinvention formulated in a compatible pharmaceutical carrier can also beprepared, placed in an appropriate container, and labeled for treatmentof an indicated condition.

It will be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe invention. Therefore, it should be clearly understood that the formsof the invention are illustrative only and are not intended to limit thescope of the invention.

Example 1

The patient suffers from an inflammatory condition related to the skin.At the time of consultation, he is otherwise healthy. He is prescribed atopical composition comprising an X-ray contrast media. Follow upreveals that the administration of the composition improves thecondition.

Example 2

The patient suffers from eczema or psoriasis. At the time ofconsultation, he is otherwise healthy. He is prescribed a topicalcomposition comprising an X-ray contrast media and an emollient. Followup reveals that the administration of the composition improves theeczema or psoriasis.

Example 3

The patient suffers from a condition related to bronchial inflammation.At the time of consultation, he is otherwise healthy. He is prescribedan aerosolized composition comprising an X-ray contrast media. Follow upreveals that the administration of the composition improves thecondition.

Example 4

The patient suffers from allergic esophagitis. At the time ofconsultation, he is otherwise healthy. He is prescribed an oralcomposition comprising an X-ray contrast media. Follow up reveals thatthe administration of the composition improves the allergic esophagitis.

Example 5

The patient suffers from a condition related to colon inflammation suchas ulcerative colitis. At the time of consultation, she is otherwisehealthy. She is prescribed an enema composition comprising an X-raycontrast media. Follow up reveals that the administration of thecomposition improves the condition.

Example 6

The patient suffers from inflammatory bowel disease such as irritablebowel syndrome. At the time of consultation, she is otherwise healthy.She is prescribed an enema composition comprising an X-ray contrastmedia. Follow up reveals that the administration of the compositionimproves the inflammatory bowel disease.

Example 7

The patient suffers from allergic esophagitis. At the time ofconsultation, she is otherwise healthy. She is prescribed an oralcomposition comprising an X-ray contrast media. Follow up reveals thatthe administration of the composition improves the allergic esophagitis.

Example 8

The patient suffers from a common cold. At the time of consultation, sheis otherwise healthy. She is prescribed a nasal composition comprisingan X-ray contrast media. Follow up reveals that the administration ofthe composition improves the cold.

Example 9

The patient suffers from nasal congestion of undetermined origin. At thetime of consultation, she is otherwise healthy. She is prescribed anasal composition comprising an X-ray contrast media. Follow up revealsthat the administration of the composition improves the nasalcongestion.

Example 10

The patient is known to have anaphylactic symptoms on injection ofvaccines or sensitizing antigens in desensitization procedures. He isprescribed a subdermal contrast media injection along with thesensitizing antigen or vaccine. Follow up reveals that theadministration of the composition inhibits the vaccine reaction or theanaphylactic reaction.

Example 11

A single-blind study was conducted using three human patients. Thepatients were exposed to cat allergen at three different dilutions,1:1,000, 1:100, and 1:10. Exposure to the 1:1,000 dilution of allergenwas showed no symptoms in the patients. Exposure to the 1:100 dilutionof allergen caused a mild reaction in all of the patients. Exposure tothe 1:10 dilution of allergen caused moderate reactions in all of thepatients, with one patient in particular requiring some treatment forthe reaction.

Patients were then pre-treated with Visipaque 320® (iodixanol). Exposureto cat allergen diluted 1:100 following the Visipaque 320 pretreatmentwas not associated with any symptoms. Exposure to allergen diluted 1:10following the Visipaque 320 pretreatment was associated with mildreactions, similar to the exposure to the 1:100 dilution without theVisipaque 320 pretreatment.

Patients were pre-treated with Iotrolan 280. Exposure to allergendiluted 1:10 following the Iotrolan 280 pretreatment was associated withmild reactions as well.

Table 2 summarizes the results and symptoms after exposure to a 1:10dilution of cat allergen both with and without pretreatment withVisipaque 320 or Iotrolan 280. The pretreatment resulted in a decreasedreaction to the cat allergen compared to the reaction withoutpretreatment.

TABLE 2 Visipaque 320 Iotrolan 280 No Pretreatment PretreatmentPretreatment Itch 11+ 1+/− 0  Drip 11+ 1+/− 1+ Congestion 11+ 2+ 1+Total 33+ 4+ 2+ Sneezes 5x 2x 2x

Example 12

A single-blind study was conducted using three human patients. Patientswere pre-treated with Visipaque 320® (Iodixanol) or not treated withcontrast media. The patients were exposed to cat allergen at threedifferent dilutions, 1:1000, 1:100, and 1:10. Patient symptoms of itch,drip, congestion, and sneeze were assessed. Tables 3-5 show the resultsand symptoms after exposure to the indicated dilution of cat allergenboth with and without pretreatment with Visipaque 320®. The pretreatmentresulted in decreased symptoms in response to the cat allergen comparedto the reaction without pretreatment.

TABLE 3 Patient 1 No Pretreatment Visipaque 320 Pretreatment 1:1000concentration cat allergen Itch 2+ 0 Drip 1+ 0 Congestion 0  0 Sneezes0  0 1:100 concentration cat allergen Itch 1+ 0 Drip 1+ 0 Congestion 1+0 Sneezes 0  0 1:10 concentration cat allergen Itch 1+ 0 Drip 3+  1+Congestion 3+  1+ Sneezes  1x+  2x

TABLE 4 Patient 2 No Pretreatment Visipaque 320 Pretreatment 1:1000concentration cat allergen Itch 1+ (eye) 0 Drip 1+ 0 Congestion 0  0Sneezes 0  0 1:100 concentration cat allergen Itch 2+ (eye) 0 Drip 2+ 0Congestion 1+ 0 Sneezes 1x 0 1:10 concentration cat allergen Itch 2+ 0Drip 2-3+ 0 Congestion 2-3+ 0 Sneezes 1x 0

TABLE 5 Patient 3 No Pretreatment Visipaque 320 Pretreatment 1:1000concentration cat allergen Itch 0  0 Drip 1+ +/− Congestion 1+ 0 Sneezes0  0 1:100 concentration cat allergen Itch 1+ 0 Drip +/− 0 Congestion 0 0 Sneezes 1x 0 1:10 concentration cat allergen Itch 1+ +/− (ear) Drip 2+0 Congestion 2+  1+ Sneezes 1x  2x

In a similar study, patients were treated with Iotrolan 280 prior toexposure to 1:10, 1:100, or 1:1000 dilutions of cat allergen. Theeffects of Iotrolan 280 treatment on the symptoms following exposure tocat allergen were similar to the effects seen with the Visipaque 320®treatment, summarized in Tables 3-5.

Example 13

FIG. 1 is a photograph showing the response of the patient to 6injections. Three substances were each injected twice at two differentlocations, for a total of 6 injections. Each substance was injected atone location that had been pretreated with Cholografin® meglumine and ata second location that had not been pretreated. Cholografin® meglumine,which comprises 80% Iodipamide in emollient, was applied topically topart of a patient's arm. 45 minutes after application of theCholografin® meglumine, each of the three substances was injected intothe two different locations on the arm, one pretreated and one that wasnot pretreated.

The three substances were histamine, dust allergen, and grass allergen.Referring to FIG. 1, the two histamine injections went into the upperlevel of the arm, the two dust allergen injections went into the middlelevel of the arm, and the two grass allergen injections went into thelower level of the arm.

FIG. 1 is a photograph showing the resulting reactions taken 2.5 hoursafter the injections. The left side of FIG. 1 shows the reactions sitescorresponding to the untreated side of the arm and the right side ofFIG. 1 show the sites corresponding to the pretreated side of the arm.

The reactions of upper, middle and lower levels of the arm on theuntreated sides were rated with scores of 3+, 4+, and 4+, respectively.The reactions of the upper, middle and lower levels of the arm on thepretreated sides were rated with scores of 1+, 2+, and 2+, respectively.The decreased reactions on the pretreated side of the arm demonstratethat iodipamide acts caused a decreased reaction to histamine, dustallergen and grass allergen.

1. A method of treating a skin inflammatory condition in a mammal inneed thereof, comprising contacting at least part of the skin of amammal with a therapeutically effective amount of a compositioncomprising an X-ray contrast media.
 2. The method of claim 1, furthercomprising identifying the mammal as a mammal that suffers from acondition related to skin inflammation or dermatitis.
 3. The method ofclaim 1, wherein the condition is selected from eczema, dermatosis,insect bite reaction, sunburn or other skin allergen reactions. 4-7.(canceled)
 8. The method of claim 3, wherein the skin allergen is acleaning solution (including shampoo), a detergent, a cosmetic, aperfume, an industrial chemical, a latex rubber, poison ivy, poison oak,poison sumac, a dust allergen, or a grass allergen.
 9. The method ofclaim 1, wherein the composition is formulated as a topical formulation.10. The method of claim 9, wherein the topical formulation comprises aformulation selected from a gel formulation, a cream formulation, alotion formulation, a paste formulation, an ointment formulation, an oilformulation, and a foam formulation.
 11. The method of claim 1, whereinthe composition further comprises an absorption emollient.
 12. Themethod of claim 1 wherein the at least part of the affected area of themammal is contacted with the composition on a daily basis. 13.(canceled)
 14. The method of claim 1, wherein the X-ray contrast mediais selected from the group consisting of either a monomeric or dimeric,nonionic or ionic contrast media.
 15. The method of claim 1, wherein theX-ray contrast media comprises triiodinated, completely or partiallysubstituted, benzene moieties existing in the form of a monomer or adimer.
 16. The method of claim 1, wherein the X-ray contrast media isselected from the group consisting of IOPAMIDOL, IOVERSOL, IOPROMIDE,IOHEXOL, IOTHALAMATE, DIATRIZOATE, IOXAGLATE, IODIPAMIDE, IODIXANOL,IOPANOIC ACID, TYROPANOATE AND IOTROLAN.
 17. A method of treatinginflammation of the upper respiratory track/bronchi in a mammal in needthereof, comprising contacting at least part of the upper respiratorytract/bronchi of a mammal with a therapeutically effective amount of acomposition comprising an X-ray contrast media.
 18. (canceled)
 19. Themethod of claim 17, wherein the composition is formulated as an aerosolformulation. 20-21. (canceled)
 22. A method of treating a coloninflammatory condition in a mammal in need thereof comprising contactingat least part of the colon of a mammal with a therapeutically effectiveamount of a composition comprising an X-ray contrast media. 23-26.(canceled)
 27. A method of treating a condition related to inflammationof the esophagus in a mammal in need thereof, comprising contacting atleast part of the esophagus of the mammal with a therapeuticallyeffective amount of a composition comprising an X-ray contrast media.28-30. (canceled)
 31. A topical composition comprising an X-ray contrastmedia and a pharmaceutically acceptable topical carrier.
 32. Thecomposition of claim 31, wherein the topical composition is formulatedas a formulation selected from a gel, a cream, a lotion, a paste, anointment, an oil, and a foam.
 33. The composition of claim 31, whereinthe composition is formulated to be substantially absorbed by anepidermal layer of the skin.
 34. The composition of claim 31, whereinthe pharmaceutically acceptable carrier is an absorption emollient. 35.The composition of claim 31, wherein the X-ray contrast media isselected from the group consisting of IOPAMIDOL, IOVERSOL, IOPROMIDE,IOHEXOL, IOTHALAMATE, DIATRIZOATE, IOXAGLATE, IODIPAMIDE, IODIXANOL,IOPANOIC ACID, TYROPANOATE AND IOTROLAN. 36-40. (canceled)
 41. A methodof treating a common cold, comprising administering a therapeuticallyeffective amount of a composition comprising an X-ray contrast media.42-44. (canceled)